Bone, Immunologic, and Virologic Effects of a Antiretroviral Regimen

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01400412
First received: July 21, 2011
Last updated: July 14, 2015
Last verified: July 2015
  Purpose

The main purpose of this study was to compare the effects on bones of the following two drug combinations:

  • maraviroc (MVC), emtricitabine (FTC), plus darunavir/ritonavir (DRV/r)
  • tenofovir (TDF) plus emtricitabine (FTC) plus darunavir/ritonavir (DRV/r)

Additional study objectives were the following:

  • To see how the drug combinations affect the brain and kidneys.
  • To see how well the drug combinations lower the HIV viral load.
  • To see how safe the drug combinations are, how well people are able to take the study drug combinations, and how well their immune systems respond to the study drugs.

Condition Intervention Phase
HIV-1 Infection
Drug: Darunavir
Drug: Ritonavir
Drug: Tenofovir disoproxil fumarate
Drug: Emtricitabine
Drug: Placebo for Tenofovir disoproxil fumarate
Drug: Placebo for Maraviroc
Drug: Maraviroc
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2b, Double-Blind, Placebo-Controlled, Exploratory Randomized Trial to Determine the Bone, Immunologic, Virologic, and Neurocognitive Effects of a Novel Maraviroc-Containing Antiretroviral Regimen in Treatment-Naïve Patients Infected With R5-Tropic HIV-1

Resource links provided by NLM:


Further study details as provided by AIDS Clinical Trials Group:

Primary Outcome Measures:
  • Percent Change From Baseline in Total Hip Bone Mineral Density (BMD) [ Time Frame: Week 0, week 48 ] [ Designated as safety issue: No ]
    The primary endpoint is the percent change in bone mineral density (BMD) at total hip (as measured by DXA scan) from baseline (week 0) to week 48.


Secondary Outcome Measures:
  • Percent Change in Lumbar Spine Bone Mineral Density (BMD) [ Time Frame: Week 0, week 48 ] [ Designated as safety issue: No ]
    The percent change in bone mineral density (BMD) at lumbar spine (as measured by DXA scan) from baseline (week 0) to week 48.

  • Change in CD4 Count From Baseline to Week 24 [ Time Frame: Week 0, week 24 ] [ Designated as safety issue: No ]
    Change in CD4 count from baseline (week 0) to week 24

  • Change in CD4 Count From Baseline to Week 48 [ Time Frame: Week 0, week 48 ] [ Designated as safety issue: No ]
    Change in CD4 count from baseline (week 0) to week 48

  • Number of Participants Who Experienced Bone Fractures [ Time Frame: From study treatment initiation to week 48 ] [ Designated as safety issue: Yes ]
    Number of participants who experienced bone fractures during the study

  • Percent Change in Expression of CD38 on CD8+ T Cells From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
    (Laboratory testing is in process and results will be entered when available.)

  • Percent Change in Expression of HLA-DR on CD8+ T Cells From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
    (Laboratory testing is in process and results will be entered when available.)

  • Percent Change in Expression of Ki67 on CD8+ T Cells From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
    (Laboratory testing is in process and results will be entered when available.)

  • Percent Change in Expression of CD28 on CD8+ T Cells From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
    (Laboratory testing is in process and results will be entered when available.)

  • Percent Change in Expression of CD57 on CD8+ T Cells From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
    (Laboratory testing is in process and results will be entered when available.)

  • Percent Change in Expression of PK1 on CD8+ T Cells From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
    (Laboratory testing is in process and results will be entered when available.)

  • Change in Levels of IL-6 From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
    (Laboratory testing is in process and results will be entered when available.)

  • Change in Level of hsCRP From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
    (Laboratory testing is in process and results will be entered when available.)

  • Change in Levels of Plasma LPS From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
    (Laboratory testing is in process and results will be entered when available.)

  • Change in Levels of Soluble CD14 From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
    (Laboratory testing is in process and results will be entered when available.)

  • Change in Level of Peripheral β7hi CD4+ T Cells From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
    (Laboratory testing is in process and results will be entered when available.)

  • Change in Levels of D-dimer From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
    (Laboratory testing is in process and results will be entered when available.)

  • CD8+ T-cell Change From Baseline [ Time Frame: At weeks 0, 24, and 48 ] [ Designated as safety issue: No ]
  • Cumulative Probability of Virologic Failure by Week 48 [ Time Frame: From study treatment initiation to week 48 ] [ Designated as safety issue: No ]

    Confirmed virologic failure is defined as confirmed plasma HIV-1 RNA levels > 1000 copies/mL at or after week 16 and before week 24, or confirmed HIV-1 RNA levels> 200 copies/mL at or after week 24. Participants who discontinued the study with an unconfirmed virologic failure (HIV-1 RNA > 1000 copies at 16 weeks or HIV-1 RNA level > 200 copies/mL at or after week 24) are considered as virologic failures at the study visit week of the unconfirmed value. Time to virologic failure is defined as the time from study entry to the planned visit week of the initial failure.

    Product-limit estimates for the survival function were used to estimate the cumulative probability of virologic failure over time and its corresponding 95% confidence interval for each treatment group.


  • Number of Participants Who Died During the Study [ Time Frame: From study treatment initiation to week 48 ] [ Designated as safety issue: Yes ]
  • Number of Participants Who Developed Grade 3 or 4 Primary Adverse Events [ Time Frame: From study treatment initiation to week 48 ] [ Designated as safety issue: Yes ]

    Grade 3 or 4 primary adverse events includes primary signs/symptoms, primary laboratory abnormalities, or primary diagnoses.

    See DAIDS AE Grading Table Version 1.0, Dec 2004 (Clarification, Aug 2009)



Enrollment: 262
Study Start Date: December 2011
Study Completion Date: June 2014
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MVC Arm: DRV/r + MVC + FTC + TDF placebo
Darunavir 800 mg PO QD + Ritonavir 100 mg PO QD + Maraviroc 150 mg PO QD + Emtricitabine 200 mg PO QD + Placebo for Tenofovir disoproxil fumarate PO QD
Drug: Darunavir
Darunavir was administered orally once a day as two 400 mg tablets with food. When the 800 mg formulation tablet became available, it was substituted for the two 400 mg tablet.
Other Names:
  • Prezista
  • TMC-114
  • DRV
Drug: Ritonavir
Ritonavir was administered orally together with darunavir as one 100 mg tablet once daily with food.
Other Names:
  • Norvir
  • RTV
Drug: Emtricitabine
Emtricitabine was administered orally once a day as one 200 mg capsule.
Other Names:
  • Emtriva
  • FTC
  • Coviracil
Drug: Placebo for Tenofovir disoproxil fumarate
Placebo for tenofovir disoproxil fumarate was administered orally once a day as one tablet.
Drug: Maraviroc
Maraviroc was administered orally once a day as one 150 mg tablet.
Other Names:
  • Celesentri
  • Selzentry
Experimental: TDF Arm: DRV/r + TDF + FTC + MVC placebo
Darunavir 800 mg PO QD + Ritonavir 100 mg PO QD + Emtricitabine 200 mg PO QD + Tenofovir disoproxil fumarate 300 mg PO QD + Placebo for Maraviroc PO QD
Drug: Darunavir
Darunavir was administered orally once a day as two 400 mg tablets with food. When the 800 mg formulation tablet became available, it was substituted for the two 400 mg tablet.
Other Names:
  • Prezista
  • TMC-114
  • DRV
Drug: Ritonavir
Ritonavir was administered orally together with darunavir as one 100 mg tablet once daily with food.
Other Names:
  • Norvir
  • RTV
Drug: Tenofovir disoproxil fumarate
Tenofovir disoproxil fumarate was administered orally as one 300 mg tablet once a day.
Other Names:
  • Viread
  • TDF
Drug: Emtricitabine
Emtricitabine was administered orally once a day as one 200 mg capsule.
Other Names:
  • Emtriva
  • FTC
  • Coviracil
Drug: Placebo for Maraviroc
Placebo for maraviroc was administered orally once a day as one tablet.

Detailed Description:

There are now several HIV treatment options for a person with HIV infection who has not yet been treated. Most people who receive treatment and take their medications as directed have a good result. This is usually determined by measuring the amount of HIV in the blood (viral load). The best response is when HIV cannot be found (less than 50 copies/mL) in the blood. However, it has recently become clear that some people with HIV who are receiving effective HIV drugs continue to have more health problems than people without HIV infection. Sometimes, there is damage to organs in the body, including bone, kidneys, and the brain.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV-1 infection
  • No evidence of exclusionary resistance mutations defined as evidence of any major NRTI mutation according to the current IAS list of HIV-1 Resistance Mutations Associated with Drug Resistance, or any DRV RAMs (refer to the A5303 PSWP for a list of these mutations) on any genotype; or evidence of significant NRTI or DRV resistance on any phenotype performed at any time prior to study entry. NNRTI-associated resistance mutations were not exclusionary.
  • ARV drug-naïve, defined as </=10 days of ART at any time prior to study entry, except in the instances defined in section 4.1.3 of the protocol.
  • R5-only tropism based on Trofile testing performed within 90 days prior to study entry.
  • Screening HIV-1 RNA >1000 copies/mL obtained within 90 days prior to study entry by any FDA-approved test for quantifying HIV-1 RNA at any laboratory that has a CLIA certification or its equivalent.
  • Known hepatitis C virus (HCV) antibody status (performed at any laboratory that had a CLIA certification or its equivalent).
  • Certain laboratory values obtained within 60 days prior to study entry, as defined in section 4.1.7 of the protocol.
  • For women of reproductive potential, negative serum or urine pregnancy test with a sensitivity of ≤25 mIU/mL within 72 hours prior to study entry.
  • Female subjects of reproductive potential, who were participating in sexual activity that could lead to pregnancy, must agree to use at least one reliable method of contraception (as defined in section 4.1.9.1 of the protocol) while receiving the study drugs and for 6 weeks after stopping the medications.
  • Female subjects who were not of reproductive potential or whose male partner(s) had azoospermia were eligible to take study drugs without the use of contraceptives.
  • Ability and willingness of subject or legal guardian/representative to give written informed consent.
  • Willingness to undergo neuropsychological testing.
  • DXA scan performed after confirmation of the subject's eligibility by Trofile testing but no more than 4 weeks prior to randomization.

Exclusion Criteria:

  • Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry.
  • New use of hormonal therapies within 6 months prior to study entry. (Stable therapy for ≥6 months was permitted.)
  • New use of oral contraceptive pills (OCPs) in the past 3 months. (Stable therapy for ≥3 months was permitted.)
  • Any oral, intravenous, or inhaled steroids within 30 days prior to study entry. (Intranasal steroids and topical corticosteroids were allowed.)
  • Known allergy/sensitivity to study drugs or their formulations. (A history of sulfa allergy was not an exclusionary condition.)
  • Known hypersensitivity to soy lecithin.
  • Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or was clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry. (Oral candidiasis, vaginal candidiasis, mucocutaneous herpes simplex, and other minor illnesses (as judged by the site investigator) were not exclusionary conditions.)
  • Requirement for any current medications that were prohibited with any study drugs. (Prohibited medications must be discontinued at least 30 days prior to entry. Refer to the A5303 PSWP for a list of prohibited medications.)
  • The presence of decompensated cirrhosis.
  • A history of or current, active HBV infection defined as positive hepatitis B surface antigen test (or positive HBV DNA in subjects with isolated HBcAb positivity, defined as negative HBsAg, negative HBsAb, and positive HBcAb) at screening.
  • Current or prior use of biphosphonates, teriparatide, raloxifene, or denosumab.
  • Weight >300 lbs (exceeds weight limit of DXA scanners).
  • History after 18 years of age of fracture of the spine, hip, wrist, or other site thought to be related to osteoporosis or bone fragility.
  • Currently breastfeeding.
  • Any active psychiatric illness including schizophrenia, severe depression, or severe bipolar affective disorder that, in the opinion of the investigator, could confound the analysis of the neurological examination or neuropsychological test results.
  • Active drug or alcohol abuse that, in the investigator's opinion, could prevent compliance with study procedures or confound the analysis of study endpoints.
  • Active brain infection (except for HIV-1), fungal meningitis, toxoplasmosis, central nervous system (CNS) lymphoma, brain neoplasm, or space-occupying brain lesion requiring acute or chronic therapy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01400412

  Show 38 Study Locations
Sponsors and Collaborators
AIDS Clinical Trials Group
Investigators
Study Chair: Babafemi Taiwo, MBBS, MD Northwestern University CRS
  More Information

No publications provided

Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT01400412     History of Changes
Other Study ID Numbers: ACTG A5303, 1U01AI068636
Study First Received: July 21, 2011
Results First Received: June 17, 2015
Last Updated: July 14, 2015
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Darunavir
Emtricitabine
Ritonavir
Tenofovir
Tenofovir disoproxil
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
HIV Protease Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Protease Inhibitors
Reverse Transcriptase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on August 30, 2015